VCV000283451.22 - ClinVar

NM_001077365.2(POMT1):c.868C>T (p.Arg290Trp)

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.

(7)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001077365.2(POMT1):c.868C>T (p.Arg290Trp)

Variation ID: 283451 Accession: VCV000283451.22

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q34.13 9: 131511349 (GRCh38) [ NCBI UCSC ] 9: 134386736 (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	Aug 27, 2017	May 1, 2024	Dec 15, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001077365.2:c.868C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001070833.1:p.Arg290Trp	missense
NM_001077366.2:c.706C>T	NP_001070834.1:p.Arg236Trp	missense
NM_001136113.2:c.868C>T	NP_001129585.1:p.Arg290Trp	missense
NM_001136114.2:c.517C>T	NP_001129586.1:p.Arg173Trp	missense
NM_001353193.2:c.934C>T	NP_001340122.2:p.Arg312Trp	missense
NM_001353194.2:c.706C>T	NP_001340123.1:p.Arg236Trp	missense
NM_001353195.2:c.517C>T	NP_001340124.1:p.Arg173Trp	missense
NM_001353196.2:c.778C>T	NP_001340125.1:p.Arg260Trp	missense
NM_001353197.2:c.772C>T	NP_001340126.2:p.Arg258Trp	missense
NM_001353198.2:c.772C>T	NP_001340127.2:p.Arg258Trp	missense
NM_001353199.2:c.583C>T	NP_001340128.2:p.Arg195Trp	missense
NM_001353200.2:c.412C>T	NP_001340129.1:p.Arg138Trp	missense
NM_001374689.1:c.851C>T	NP_001361618.1:p.Ser284Leu	missense
NM_001374690.1:c.868C>T	NP_001361619.1:p.Arg290Trp	missense
NM_001374691.1:c.517C>T	NP_001361620.1:p.Arg173Trp	missense
NM_001374692.1:c.517C>T	NP_001361621.1:p.Arg173Trp	missense
NM_001374693.1:c.706C>T	NP_001361622.1:p.Arg236Trp	missense
NM_001374695.1:c.478C>T	NP_001361624.1:p.Arg160Trp	missense
NM_007171.4:c.934C>T	NP_009102.4:p.Arg312Trp	missense
NR_148391.2:n.902C>T		non-coding transcript variant
NR_148392.2:n.1120C>T		non-coding transcript variant
NR_148393.2:n.902C>T		non-coding transcript variant
NR_148394.2:n.790C>T		non-coding transcript variant
NR_148395.2:n.1054C>T		non-coding transcript variant
NR_148396.2:n.683C>T		non-coding transcript variant
NR_148397.2:n.947C>T		non-coding transcript variant
NR_148398.2:n.902C>T		non-coding transcript variant
NR_148399.2:n.1294C>T		non-coding transcript variant
NR_148400.2:n.888C>T		non-coding transcript variant
NC_000009.12:g.131511349C>T
NC_000009.11:g.134386736C>T
NG_008896.1:g.13448C>T
LRG_842t1:c.934C>T	LRG_842p1:p.Arg312Trp
LRG_842t2:c.868C>T	LRG_842p2:p.Arg290Trp

... more HGVS ... less HGVS

Protein change

R312W, R195W, R173W, R258W, R260W, R138W, R236W, R290W, S284L, R160W

Other names

Canonical SPDI

NC_000009.12:131511348: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 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD) 0.00005

Links

ClinGen: CA10604495 dbSNP: rs886042627 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.
POMT1		-	-	GRCh38 GRCh37	1164	1205

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.
not specified	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 31, 2017	RCV000332052.14
Autosomal recessive limb-girdle muscular dystrophy type 2K Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 Walker-Warburg congenital muscular dystrophy	Uncertain significance (1)	criteria provided, single submitter	Sep 27, 2022	RCV000648159.9
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Feb 8, 2023	RCV000725271.8
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Dec 15, 2023	RCV004021137.1

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.
Uncertain significance (Dec 28, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000596533.1 First in ClinVar: Aug 27, 2017 Last updated: Aug 27, 2017
Uncertain significance (Oct 22, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000335534.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POMT1 Number of individuals with the variant: 1 Sex: mixed
Uncertain significance (Dec 19, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000534415.4 First in ClinVar: Mar 08, 2017 Last updated: Apr 17, 2019	Comment: The R312W variant in the POMT1 gene has not been published as a pathogenic variant, nor as a benign variant, to our knowledge. The R312W … (more) The R312W variant in the POMT1 gene has not been published as a pathogenic variant, nor as a benign variant, to our knowledge. The R312W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R312W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret R312W as a variant of uncertain significance. (less)
Uncertain significance (Aug 31, 2017)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000712538.2 First in ClinVar: Apr 09, 2018 Last updated: Apr 17, 2019	Comment: The p.Arg312Trp variant in POMT1 has not been previously reported in individuals with myopathy but has been identified in 5 /277130 chromosomes by the Genome … (more) The p.Arg312Trp variant in POMT1 has not been previously reported in individuals with myopathy but has been identified in 5 /277130 chromosomes by the Genome Ag gregation Database (gnomAD, http://gnomad.broadinstitute.org). Computational pre diction tools and conservation analysis suggest that the p.Arg312Trp variant may impact the protein, though this information is not predictive enough to determi ne pathogenicity. In summary, the clinical significance of the p.Arg312Trp varia nt is uncertain. (less) Number of individuals with the variant: 2
Uncertain significance (Sep 27, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 Walker-Warburg congenital muscular dystrophy Autosomal recessive limb-girdle muscular dystrophy type 2K Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000769973.5 First in ClinVar: May 28, 2018 Last updated: Feb 07, 2023	Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 312 of the POMT1 protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 312 of the POMT1 protein (p.Arg312Trp). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with POMT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 283451). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Feb 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004236452.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Uncertain significance (Dec 15, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005008718.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: The c.934C>T (p.R312W) alteration is located in exon 10 (coding exon 9) of the POMT1 gene. This alteration results from a C to T substitution … (more) The c.934C>T (p.R312W) alteration is located in exon 10 (coding exon 9) of the POMT1 gene. This alteration results from a C to T substitution at nucleotide position 934, causing the arginine (R) at amino acid position 312 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)

Comment:

The R312W variant in the POMT1 gene has not been published as a pathogenic variant, nor as a benign variant, to our knowledge. The R312W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R312W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret R312W as a variant of uncertain significance.

Comment:

The p.Arg312Trp variant in POMT1 has not been previously reported in individuals with myopathy but has been identified in 5 /277130 chromosomes by the Genome Ag gregation Database (gnomAD, http://gnomad.broadinstitute.org). Computational pre diction tools and conservation analysis suggest that the p.Arg312Trp variant may impact the protein, though this information is not predictive enough to determi ne pathogenicity. In summary, the clinical significance of the p.Arg312Trp varia nt is uncertain.

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 312 of the POMT1 protein (p.Arg312Trp). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with POMT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 283451). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The c.934C>T (p.R312W) alteration is located in exon 10 (coding exon 9) of the POMT1 gene. This alteration results from a C to T substitution at nucleotide position 934, causing the arginine (R) at amino acid position 312 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POMT1	-	-	-	-

Text-mined citations for rs886042627 ...

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_001077365.2(POMT1):c.868C>T (p.Arg290Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886042627 ...