Submissions for variant NM_001130987.2(DYSF):c.4702C>T (p.Arg1568Trp)

gnomAD frequency: 0.00005  dbSNP: rs375698433

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000647982	SCV000769792	uncertain significance	Qualitative or quantitative defects of dysferlin	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1529 of the DYSF protein (p.Arg1529Trp). This variant is present in population databases (rs375698433, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive limb girdle muscular dystrophy, type 2B (PMID: 17994539). ClinVar contains an entry for this variant (Variation ID: 538620). 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) performed at Invitae indicates that this missense variant is expected to disrupt DYSF protein function. 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.
Counsyl	RCV000669328	SCV000794072	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2B	2017-09-08	criteria provided, single submitter	clinical testing
GeneDx	RCV001785690	SCV002027881	uncertain significance	not provided	2021-05-20	criteria provided, single submitter	clinical testing	Reported in a patient with LGMD in published literature (Guglieri et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17994539)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252192	SCV002523128	uncertain significance	See cases	2021-04-14	criteria provided, single submitter	clinical testing	ACMG classification criteria: PP3
CeGaT Center for Human Genetics Tuebingen	RCV001785690	SCV004154970	uncertain significance	not provided	2022-10-01	criteria provided, single submitter	clinical testing	DYSF: PM2, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488761	SCV004241132	uncertain significance	not specified	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: DYSF c.4585C>T (p.Arg1529Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251482 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4585C>T has been reported as a single change in DYSF in one individual affected with Limb-Girdle Muscular Dystrophy,2B, without strong evidence for causality (example, Guglieri_2008). These report(s) do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 17994539). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000669328	SCV001452779	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2B	2020-09-16	no assertion criteria provided	clinical testing