Submissions for variant NM_001130987.2(DYSF):c.4629C>G (p.Val1543=)

gnomAD frequency: 0.00109  dbSNP: rs142483266

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen	RCV004998382	SCV005620333	likely benign	Autosomal recessive limb-girdle muscular dystrophy	2025-01-09	reviewed by expert panel	curation	The NM_003494.4: c.4512C>G p.(Val1504=) variant in DYSF, which is also known as NM_001130987.2: c.4629C>G p.(Val1543=), is a synonymous (silent) variant that is not expected to change the amino acid sequence. The filtering allele frequency for this variant is 0.001985 for the European (non-Finnish) population in gnomAD v4.1.0 (the lower threshold of the 95% CI of 2286/1111986 exome chromosomes), which is greater than the ClinGen LGMD VCEP threshold of 0.001 for BS1, and therefore meets this criterion (BS1). While this variant affects the first amino acid of exon 42 and so is located in a splice region (BP7 not met), the SpliceAI score is 0, which is less than the LGMD VCEP threshold of 0.05 (BP4). This variant has been identified in a patient with a clinical suspicion of LGMD but as a single hit in an individual with an alternative molecular diagnosis (LOVD Individual #00220067). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BS1, BP4.
PreventionGenetics, part of Exact Sciences	RCV000245997	SCV000309690	likely benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000724977	SCV000332842	uncertain significance	not provided	2015-07-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000724977	SCV000531550	likely benign	not provided	2018-04-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083095	SCV000649700	likely benign	Qualitative or quantitative defects of dysferlin	2025-01-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001083095	SCV001298023	uncertain significance	Qualitative or quantitative defects of dysferlin	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Athena Diagnostics	RCV000724977	SCV001477227	likely benign	not provided	2019-10-28	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001274844	SCV001459360	likely benign	Autosomal recessive limb-girdle muscular dystrophy type 2B	2019-11-11	no assertion criteria provided	clinical testing