VCV000243025.14 - ClinVar

NM_152328.5(ADSS1):c.781G>A (p.Asp261Asn)

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/Likely 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_152328.5(ADSS1):c.781G>A (p.Asp261Asn)

Variation ID: 243025 Accession: VCV000243025.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q32.33 14: 104741231 (GRCh38) [ NCBI UCSC ] 14: 105207568 (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	Jul 25, 2016	Nov 20, 2023	Jan 30, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_152328.5:c.781G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_689541.1:p.Asp261Asn	missense
NM_001320424.1:c.166G>A	NP_001307353.1:p.Asp56Asn	missense
NM_199165.2:c.910G>A	NP_954634.1:p.Asp304Asn	missense
NC_000014.9:g.104741231G>A
NC_000014.8:g.105207568G>A
NG_051175.1:g.22035G>A
	Q8N142:p.Asp261Asn

... more HGVS ... less HGVS

Protein change

D304N, D261N, D56N

Other names

NM_199165.2(ADSS1):c.910G>A

Canonical SPDI

NC_000014.9:104741230:G:A

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00003

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA7373844 UniProtKB: Q8N142#VAR_076998 OMIM: 612498.0001 OMIM: 612498.0005 dbSNP: rs140614802 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.
ADSS1		-	-	GRCh38 GRCh37	398	484

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.
Myopathy, distal, 5	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	May 4, 2022	RCV000235016.12
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 24, 2022	RCV001589201.6
ADSS1-related disorder	Pathogenic (1)	criteria provided, single submitter	Jan 30, 2023	RCV003401191.4

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 (Jan 09, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myopathy, distal, 5 (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV000837707.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018	Number of individuals with the variant: 1 Clinical Features: Ptosis (present) , Proximal muscle weakness (present) , Keratoconjunctivitis sicca (present) , Facial palsy (present) , Elbow flexion contracture (present) , Distal muscle weakness (present) … (more) Ptosis (present) , Proximal muscle weakness (present) , Keratoconjunctivitis sicca (present) , Facial palsy (present) , Elbow flexion contracture (present) , Distal muscle weakness (present) , Primary dilated cardiomyopathy (present) , Blepharospasm (present) , Atrophic scars (present) (less) Age: 30-39 years Sex: male Ethnicity/Population group: Asian/Indian Testing laboratory: HudsonAlpha Clinical Services Lab, LLC,HudsonAlpha Clinical Services Lab, LLC Date variant was reported to submitter: 2018-01-09 Testing laboratory interpretation: Pathogenic
Pathogenic (Mar 18, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001825457.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Comment: Published functional studies demonstrate a damaging effect with reduced enzymatic activity compared to the wild type in vitro. In addition, D304N mRNAs injected into zebrafish … (more) Published functional studies demonstrate a damaging effect with reduced enzymatic activity compared to the wild type in vitro. In addition, D304N mRNAs injected into zebrafish embryos resulted in a defective skeletal muscle phenotype (Park et al., 2016); This variant is associated with the following publications: (PMID: 32646962, 32331917, 30853170, 28268051, 26506222) (less)
Pathogenic (Mar 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myopathy, distal, 5 Affected status: yes Allele origin: germline	3billion Accession: SCV002318713.1 First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022	Publications: PubMed (1) PubMed: 26506222 Comment: Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000243025, PMID:26506222). The variant … (more) Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000243025, PMID:26506222). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 26506222) and co-segregated with Myopathy, distal, 5 in multiple affected family members (PMID: 26506222). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PS3_S). A missense variant is a common mechanism associated with Myopathy, distal, 5. The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000340). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Muscular dystrophy (present) , Myopathic facies (present)
Likely pathogenic (May 04, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Myopathy, distal, 5 (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV002507011.1 First in ClinVar: May 16, 2022 Last updated: May 16, 2022	Comment: The homozygous p.Asp304Asn variant in ADSS1 was identified by our study in 1 individual with distal myopathy 5. The variant has been reported in 4 … (more) The homozygous p.Asp304Asn variant in ADSS1 was identified by our study in 1 individual with distal myopathy 5. The variant has been reported in 4 Korean individuals with distal myopathy 5 (PMID: 26506222), segregated with disease in 4 affected relatives from 2 families (PMID: 26506222), and has been identified in 0.01% (4/28258) of South Asian, 0.01% (2/17392) of East Asian, and 0.006% (1/15946) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs140614802). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 243025) as pathogenic by NIH Undiagnosed Diseases Network and OMIM, and as likely pathogenic by Fulgent Genetics. Animal models in zebrafish have shown that this variant causes distal myopathy 5 (PMID: 26506222). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in 1 affected homozygote, in combination with a reported variant of uncertain significance that is confirmed in trans, and in 4 individuals with distal myopathy 5 increases the likelihood that the p.Asp304Asn variant is pathogenic (Variation ID: 243026, PMID: 26506222). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM3, PP1 (Richards 2015). (less)
Likely pathogenic (Jan 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myopathy, distal, 5 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893336.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Oct 24, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002509970.2 First in ClinVar: May 16, 2022 Last updated: Feb 07, 2023	Publications: PubMed (2) PubMed: 26506222‚ 32331917 Comment: This sequence change replaces aspartic acid with asparagine at codon 304 of the ADSSL1 protein (p.Asp304Asn). This variant is present in population databases (rs140614802, gnomAD … (more) This sequence change replaces aspartic acid with asparagine at codon 304 of the ADSSL1 protein (p.Asp304Asn). This variant is present in population databases (rs140614802, gnomAD 0.01%). This missense change has been observed in individuals with distal myopathy (PMID: 26506222, 32331917). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 243025). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). Experimental studies have shown that this missense change affects ADSSL1 function (PMID: 26506222). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 30, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ADSS1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004105375.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The ADSS1 c.910G>A variant is predicted to result in the amino acid substitution p.Asp304Asn. This variant was reported in the homozygous and compound heterozygous states … (more) The ADSS1 c.910G>A variant is predicted to result in the amino acid substitution p.Asp304Asn. This variant was reported in the homozygous and compound heterozygous states in multiple individuals with myopathy (Mroczek et al. 2020. PubMed ID: 32331917; Park et al. 2016. PubMed ID: 26506222). Functional studies showed the the variant led to decreased enzyme activity (Park et al. 2016. PubMed ID: 26506222). This variant is reported in 0.014% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-105207568-G-A). This variant is interpreted as pathogenic. (less)
Pathogenic (Jul 15, 2016)	no assertion criteria provided Method: literature only	MYOPATHY, DISTAL, 5 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000292394.1 First in ClinVar: Jul 25, 2016 Last updated: Jul 25, 2016	Publications: PubMed (1) PubMed: 26506222 Comment on evidence: In 4 patients from 2 unrelated Korean families with distal myopathy-5 (MPD5; 617030), Park et al. (2016) identified compound heterozygous mutations in the ADSSL1 gene: … (more) In 4 patients from 2 unrelated Korean families with distal myopathy-5 (MPD5; 617030), Park et al. (2016) identified compound heterozygous mutations in the ADSSL1 gene: a c.910G-A transition, resulting in an asp304-to-asn (D304N) substitution at a highly conserved residue in the synthase domain, and a 1-bp deletion (c.1048delA; 612498.0002), resulting in a frameshift, premature termination (Ile350fs), and loss of GTP-binding sites. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Both variants were present at very low frequencies in the dbSNP (build 142) and Exome Variant Server databases, but were not found in 500 Korean controls. Haplotype analysis suggested a founder effect for both mutations. Patient muscle samples showed decreased expression of the mutant missense protein and no expression of the truncated protein, which was attributed to increased degradation of the mutant proteins. Cultured mouse muscle cells transfected with the mutations showed that both significantly decreased the synthesis of adenylosuccinate. Neither mutation was able to rescue reduced cell viability in muscle cells treated with siRNA ADSSL1 knockdown or muscle defects in adssl1-null zebrafish, consistent with a loss of function. These findings indicated that ADSSL1 in crucial for muscle cell viability. (less)
not provided (-)	no classification provided Method: phenotyping only	Myopathy, distal, 5 Affected status: yes Allele origin: germline	GenomeConnect, ClinGen Accession: SCV003761506.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Comment: Homozygous variant classified as Pathogenic and reported on 10-19-2017 by Lab or GTR ID 505801. GenomeConnect assertions are reported exactly as they appear on the … (more) Homozygous variant classified as Pathogenic and reported on 10-19-2017 by Lab or GTR ID 505801. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Distal muscle weakness (present) , Weakness of facial musculature (present) , Ptosis (present) , Primary dilated cardiomyopathy (present) , Muscular dystrophy (present) Indication for testing: Diagnostic Age: 30-39 years Sex: male Method: Genome Sequencing Testing laboratory: HudsonAlpha Clinical Services Lab, LLC,HudsonAlpha Clinical Services Lab, LLC Date variant was reported to submitter: 2017-10-19 Testing laboratory interpretation: Pathogenic

Comment:

Published functional studies demonstrate a damaging effect with reduced enzymatic activity compared to the wild type in vitro. In addition, D304N mRNAs injected into zebrafish embryos resulted in a defective skeletal muscle phenotype (Park et al., 2016); This variant is associated with the following publications: (PMID: 32646962, 32331917, 30853170, 28268051, 26506222)

Comment:

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000243025, PMID:26506222). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 26506222) and co-segregated with Myopathy, distal, 5 in multiple affected family members (PMID: 26506222). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PS3_S). A missense variant is a common mechanism associated with Myopathy, distal, 5. The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000340). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The homozygous p.Asp304Asn variant in ADSS1 was identified by our study in 1 individual with distal myopathy 5. The variant has been reported in 4 Korean individuals with distal myopathy 5 (PMID: 26506222), segregated with disease in 4 affected relatives from 2 families (PMID: 26506222), and has been identified in 0.01% (4/28258) of South Asian, 0.01% (2/17392) of East Asian, and 0.006% (1/15946) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs140614802). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 243025) as pathogenic by NIH Undiagnosed Diseases Network and OMIM, and as likely pathogenic by Fulgent Genetics. Animal models in zebrafish have shown that this variant causes distal myopathy 5 (PMID: 26506222). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in 1 affected homozygote, in combination with a reported variant of uncertain significance that is confirmed in trans, and in 4 individuals with distal myopathy 5 increases the likelihood that the p.Asp304Asn variant is pathogenic (Variation ID: 243026, PMID: 26506222). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM3, PP1 (Richards 2015).

Comment:

This sequence change replaces aspartic acid with asparagine at codon 304 of the ADSSL1 protein (p.Asp304Asn). This variant is present in population databases (rs140614802, gnomAD 0.01%). This missense change has been observed in individuals with distal myopathy (PMID: 26506222, 32331917). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 243025). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). Experimental studies have shown that this missense change affects ADSSL1 function (PMID: 26506222). For these reasons, this variant has been classified as Pathogenic.

Comment:

The ADSS1 c.910G>A variant is predicted to result in the amino acid substitution p.Asp304Asn. This variant was reported in the homozygous and compound heterozygous states in multiple individuals with myopathy (Mroczek et al. 2020. PubMed ID: 32331917; Park et al. 2016. PubMed ID: 26506222). Functional studies showed the the variant led to decreased enzyme activity (Park et al. 2016. PubMed ID: 26506222). This variant is reported in 0.014% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-105207568-G-A). This variant is interpreted as pathogenic.

Comment:

Homozygous variant classified as Pathogenic and reported on 10-19-2017 by Lab or GTR ID 505801. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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
Expanding the disease phenotype of ADSSL1-associated myopathy in non-Korean patients.	Mroczek M	Neuromuscular disorders : NMD	2020	PMID: 32331917
ADSSL1 mutation relevant to autosomal recessive adolescent onset distal myopathy.	Park HJ	Annals of neurology	2016	PMID: 26506222

Text-mined citations for rs140614802 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_152328.5(ADSS1):c.781G>A (p.Asp261Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs140614802 ...