VCV000533814.38 - ClinVar

NM_001540.5(HSPB1):c.116C>T (p.Pro39Leu)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(9)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001540.5(HSPB1):c.116C>T (p.Pro39Leu)

Variation ID: 533814 Accession: VCV000533814.38

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q11.23 7: 76302828 (GRCh38) [ NCBI UCSC ] 7: 75932145 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 28, 2018	Oct 20, 2024	Dec 28, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001540.5:c.116C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001531.1:p.Pro39Leu	missense
NC_000007.14:g.76302828C>T
NC_000007.13:g.75932145C>T
NG_008995.1:g.5271C>T
LRG_248:g.5271C>T
LRG_248t1:c.116C>T

... more HGVS ... less HGVS

Protein change

P39L

Other names

Canonical SPDI

NC_000007.14:76302827:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA4306259 dbSNP: rs557327165 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
HSPB1		-	-	GRCh38 GRCh37	370	410

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Charcot-Marie-Tooth disease axonal type 2F	Pathogenic (1)	criteria provided, single submitter	Dec 28, 2023	RCV000641079.9
Charcot-Marie-Tooth disease	Pathogenic (2)	criteria provided, single submitter	-	RCV000789058.3
Neuronopathy, distal hereditary motor, type 2B	Pathogenic (1)	criteria provided, single submitter	Jan 24, 2019	RCV001197515.3
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Nov 1, 2022	RCV002060745.22
HSPB1-related axonal neuropathies	Pathogenic (1)	criteria provided, single submitter	Jun 16, 2021	RCV001796974.5
HSPB1-related disorder	Pathogenic (1)	no assertion criteria provided	Mar 5, 2024	RCV004544855.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease Affected status: yes Allele origin: germline	Molecular Genetics Laboratory, London Health Sciences Centre Accession: SCV001337299.1 First in ClinVar: Jun 14, 2020 Last updated: Jun 14, 2020
Pathogenic (Jan 24, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronopathy, distal hereditary motor, type 2B Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368291.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3.
Pathogenic (Jun 16, 2021)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	HSPB1-related axonal neuropathies Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV002038568.1 First in ClinVar: Dec 23, 2021 Last updated: Dec 23, 2021	Publications: PubMed (5) PubMed: 22176143‚ 25965061‚ 28144995‚ 28595321‚ 29381233 Comment: The HSPB1 c.116C>T (p.Pro39Leu) variant is a missense variant that has been reported in at least three studies, in which it was found in a … (more) The HSPB1 c.116C>T (p.Pro39Leu) variant is a missense variant that has been reported in at least three studies, in which it was found in a heterozygous state in at least eight unrelated individuals with Charcot-Marie-Tooth disease type 2 or distal hereditary motor neuropathy (Capponi et al. 2011; Echaniz-Laguna et al. 2017; Tanabe et al. 2018). In several families, multiple affected individuals were heterozygous for the variant and in at least one individual, the variant was shown to be de novo. The p.Pro39Leu variant is reported at a frequency of 0.00001 in the European (non-Finnish) population from the Genome Aggregation Database (version 2.1.1), though this is based on one allele in a region of good sequence coverage, so the variant is presumed to be rare. Physicochemical studies of the p.Pro39Leu variant noted a decrease in phosphorylation-dependent dissociation of large oligomers and decreased chaperoning activity compared to wildtype (Muranova et al. 2015). Furthermore, the p.Pro39Leu variant was associated with mitochondrial dysfunction in motor neurons and increased vulnerability to oxidative stress (Kalmar et al. 2017). Based on the available evidence, the p.Pro39Leu variant is classified as pathogenic for HSPB1-related axonal neuropathies. (less)
Pathogenic (Sep 09, 2021)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV002770664.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Publications: PubMed (18) PubMed: 28144995‚ 27816334‚ 22176143‚ 28595321‚ 25965061‚ 29381233‚ 26077850‚ 24719117‚ 31573509‚ 22484489‚ 32301006‚ 32323160‚ 25999205‚ 21971574‚ 30758704‚ 24607769‚ 23379525‚ 18832141 Comment: The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical … (more) The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant appears to occur de novo in one individual with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Expression of this variant in a motor neuron cell line resulted in impaired mitochondrial function and transport (PMID: 28592321). (less)
Pathogenic (Apr 18, 2022)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV003800118.2 First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023	Comment: The HSBP1 c.116C>T; p.Pro39Leu variant (rs557327165) is reported in the literature in multiple individuals and families affected with Charcot-Marie-Tooth disease type 2 and distal hereditary … (more) The HSBP1 c.116C>T; p.Pro39Leu variant (rs557327165) is reported in the literature in multiple individuals and families affected with Charcot-Marie-Tooth disease type 2 and distal hereditary motor neuropathy (Capponi 2011, Echaniz-Laguna 2017, Kalmar 2017, Rossor 2017). Functional analyses of the variant protein show increased protein aggregation, increased resistance to dissociation, reduced chaperone-like activity (Muranova 2015) and mitochondrial dysfunction (Kalmer 2017). This variant is reported in ClinVar (Variation ID: 533814) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic. References: Capponi S et al. HSPB1 and HSPB8 in inherited neuropathies: study of an Italian cohort of dHMN and CMT2 patients. J Peripher Nerv Syst. 2011 Dec;16(4):287-94. PMID: 22176143. Echaniz-Laguna A et al. Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations. Hum Mutat. 2017 May;38(5):556-568. PMID: 28144995. Kalmar B et al. Mitochondrial deficits and abnormal mitochondrial retrograde axonal transport play a role in the pathogenesis of mutant Hsp27-induced Charcot Marie Tooth Disease. Hum Mol Genet. 2017 Sep 1;26(17):3313-3326. PMID: 28595321. Muranova et al. Characterization of Mutants of Human Small Heat Shock Protein HspB1 Carrying Replacements in the N-Terminal Domain and Associated with Hereditary Motor Neuron Diseases. PLoS One. 2015 May 12;10(5):e0126248. PMID: 25965061. Rossor AM et al. Pilot phenotype and natural history study of hereditary neuropathies caused by mutations in the HSPB1 gene. Neuromuscul Disord. 2017 Jan;27(1):50-56. PMID: 27816334. (less)
Pathogenic (Dec 28, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth disease axonal type 2F Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000762697.7 First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 22176143‚ 27816334‚ 28144995‚ 25965061‚ 28595321 Comment: This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 39 of the HSPB1 protein (p.Pro39Leu). … (more) This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 39 of the HSPB1 protein (p.Pro39Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease (PMID: 22176143, 27816334, 28144995). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 533814). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HSPB1 protein function. Experimental studies have shown that this missense change affects HSPB1 function (PMID: 25965061, 28595321). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Nov 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002497523.18 First in ClinVar: Apr 08, 2022 Last updated: Oct 20, 2024	Comment: HSPB1: PP1:Strong, PM2, PS4:Moderate, PP4, PS3:Supporting Number of individuals with the variant: 2
Uncertain significance (-)	no assertion criteria provided Method: literature only	Charcot-Marie-Tooth disease Affected status: yes Allele origin: germline	Inherited Neuropathy Consortium Accession: SCV000928407.1 First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019	Publications: PubMed (1) PubMed: 18832141
Pathogenic (Mar 05, 2024)	no assertion criteria provided Method: clinical testing	HSPB1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004764438.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The HSPB1 c.116C>T variant is predicted to result in the amino acid substitution p.Pro39Leu. This variant was reported in individuals with autosomal dominant Charcot-Marie-Tooth disease, … (more) The HSPB1 c.116C>T variant is predicted to result in the amino acid substitution p.Pro39Leu. This variant was reported in individuals with autosomal dominant Charcot-Marie-Tooth disease, type 2 (Houlden et al 2008. PubMed ID: 18832141; Volodarsky et al 2020. PubMed ID: 32376792; Tanabe et al. 2018. PubMed ID: 29381233). Functional studies suggest that the p.Pro39Leu variant led to abnormal mitochondrial axonal transport and abnormal phosphorylation (Kalmar et al 2017. PubMed ID: 28595321; Muranova et al 2015. PubMed ID: 25965061). This variant is reported in 0.00099% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)

Comment:

The HSPB1 c.116C>T (p.Pro39Leu) variant is a missense variant that has been reported in at least three studies, in which it was found in a heterozygous state in at least eight unrelated individuals with Charcot-Marie-Tooth disease type 2 or distal hereditary motor neuropathy (Capponi et al. 2011; Echaniz-Laguna et al. 2017; Tanabe et al. 2018). In several families, multiple affected individuals were heterozygous for the variant and in at least one individual, the variant was shown to be de novo. The p.Pro39Leu variant is reported at a frequency of 0.00001 in the European (non-Finnish) population from the Genome Aggregation Database (version 2.1.1), though this is based on one allele in a region of good sequence coverage, so the variant is presumed to be rare. Physicochemical studies of the p.Pro39Leu variant noted a decrease in phosphorylation-dependent dissociation of large oligomers and decreased chaperoning activity compared to wildtype (Muranova et al. 2015). Furthermore, the p.Pro39Leu variant was associated with mitochondrial dysfunction in motor neurons and increased vulnerability to oxidative stress (Kalmar et al. 2017). Based on the available evidence, the p.Pro39Leu variant is classified as pathogenic for HSPB1-related axonal neuropathies.

Comment:

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant appears to occur de novo in one individual with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Expression of this variant in a motor neuron cell line resulted in impaired mitochondrial function and transport (PMID: 28592321).

Comment:

The HSBP1 c.116C>T; p.Pro39Leu variant (rs557327165) is reported in the literature in multiple individuals and families affected with Charcot-Marie-Tooth disease type 2 and distal hereditary motor neuropathy (Capponi 2011, Echaniz-Laguna 2017, Kalmar 2017, Rossor 2017). Functional analyses of the variant protein show increased protein aggregation, increased resistance to dissociation, reduced chaperone-like activity (Muranova 2015) and mitochondrial dysfunction (Kalmer 2017). This variant is reported in ClinVar (Variation ID: 533814) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic. References: Capponi S et al. HSPB1 and HSPB8 in inherited neuropathies: study of an Italian cohort of dHMN and CMT2 patients. J Peripher Nerv Syst. 2011 Dec;16(4):287-94. PMID: 22176143. Echaniz-Laguna A et al. Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations. Hum Mutat. 2017 May;38(5):556-568. PMID: 28144995. Kalmar B et al. Mitochondrial deficits and abnormal mitochondrial retrograde axonal transport play a role in the pathogenesis of mutant Hsp27-induced Charcot Marie Tooth Disease. Hum Mol Genet. 2017 Sep 1;26(17):3313-3326. PMID: 28595321. Muranova et al. Characterization of Mutants of Human Small Heat Shock Protein HspB1 Carrying Replacements in the N-Terminal Domain and Associated with Hereditary Motor Neuron Diseases. PLoS One. 2015 May 12;10(5):e0126248. PMID: 25965061. Rossor AM et al. Pilot phenotype and natural history study of hereditary neuropathies caused by mutations in the HSPB1 gene. Neuromuscul Disord. 2017 Jan;27(1):50-56. PMID: 27816334.

Comment:

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 39 of the HSPB1 protein (p.Pro39Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease (PMID: 22176143, 27816334, 28144995). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 533814). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HSPB1 protein function. Experimental studies have shown that this missense change affects HSPB1 function (PMID: 25965061, 28595321). For these reasons, this variant has been classified as Pathogenic.

Comment:

The HSPB1 c.116C>T variant is predicted to result in the amino acid substitution p.Pro39Leu. This variant was reported in individuals with autosomal dominant Charcot-Marie-Tooth disease, type 2 (Houlden et al 2008. PubMed ID: 18832141; Volodarsky et al 2020. PubMed ID: 32376792; Tanabe et al. 2018. PubMed ID: 29381233). Functional studies suggest that the p.Pro39Leu variant led to abnormal mitochondrial axonal transport and abnormal phosphorylation (Kalmar et al 2017. PubMed ID: 28595321; Muranova et al 2015. PubMed ID: 25965061). This variant is reported in 0.00099% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Small heat shock proteins in neurodegenerative diseases.	Vendredy L	Cell stress & chaperones	2020	PMID: 32323160
Mutations in HspB1 and hereditary neuropathies.	Muranova LK	Cell stress & chaperones	2020	PMID: 32301006
Interplay of disordered and ordered regions of a human small heat shock protein yields an ensemble of 'quasi-ordered' states.	Clouser AF	eLife	2019	PMID: 31573509
Small heat shock proteins: multifaceted proteins with important implications for life.	Carra S	Cell stress & chaperones	2019	PMID: 30758704
Clinical and genetic features of Charcot-Marie-Tooth disease 2F and hereditary motor neuropathy 2B in Japan.	Tanabe H	Journal of the peripheral nervous system : JPNS	2018	PMID: 29381233
Mitochondrial deficits and abnormal mitochondrial retrograde axonal transport play a role in the pathogenesis of mutant Hsp27-induced Charcot Marie Tooth Disease.	Kalmar B	Human molecular genetics	2017	PMID: 28595321
Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations.	Echaniz-Laguna A	Human mutation	2017	PMID: 28144995
Pilot phenotype and natural history study of hereditary neuropathies caused by mutations in the HSPB1 gene.	Rossor AM	Neuromuscular disorders : NMD	2017	PMID: 27816334
High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders.	Yavarna T	Human genetics	2015	PMID: 26077850
In silico evaluation of human small heat shock protein HSP27: homology modeling, mutation analyses and docking studies.	Fossa P	Bioorganic & medicinal chemistry	2015	PMID: 25999205
Characterization of Mutants of Human Small Heat Shock Protein HspB1 Carrying Replacements in the N-Terminal Domain and Associated with Hereditary Motor Neuron Diseases.	Muranova LK	PloS one	2015	PMID: 25965061
Barcoding heat shock proteins to human diseases: looking beyond the heat shock response.	Kakkar V	Disease models & mechanisms	2014	PMID: 24719117
Neuropathy- and myopathy-associated mutations in human small heat shock proteins: Characteristics and evolutionary history of the mutation sites.	Benndorf R	Mutation research. Reviews in mutation research	2014	PMID: 24607769
Mutations of small heat shock proteins and human congenital diseases.	Datskevich PN	Biochemistry. Biokhimiia	2012	PMID: 23379525
The family of mammalian small heat shock proteins (HSPBs): implications in protein deposit diseases and motor neuropathies.	Boncoraglio A	The international journal of biochemistry & cell biology	2012	PMID: 22484489
Alteration of protein folding and degradation in motor neuron diseases: Implications and protective functions of small heat shock proteins.	Carra S	Progress in neurobiology	2012	PMID: 21971574
HSPB1 and HSPB8 in inherited neuropathies: study of an Italian cohort of dHMN and CMT2 patients.	Capponi S	Journal of the peripheral nervous system : JPNS	2011	PMID: 22176143
Mutations in the HSP27 (HSPB1) gene cause dominant, recessive, and sporadic distal HMN/CMT type 2.	Houlden H	Neurology	2008	PMID: 18832141
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Text-mined citations for rs557327165 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001540.5(HSPB1):c.116C>T (p.Pro39Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs557327165 ...