Submissions for variant NM_004393.6(DAG1):c.2326C>T (p.Arg776Cys)

gnomAD frequency: 0.00004  dbSNP: rs752441031

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000393636	SCV000340078	uncertain significance	not provided	2016-03-10	criteria provided, single submitter	clinical testing
Invitae	RCV000807544	SCV000947601	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2P; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 776 of the DAG1 protein (p.Arg776Cys). This variant is present in population databases (rs752441031, gnomAD 0.009%). This missense change has been observed in individual(s) with autosomal recessive muscular dystrophy‚Äêdystroglycanopathy (PMID: 30450679). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 286590). 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 DAG1 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387825	SCV004100023	uncertain significance	not specified	2023-09-20	criteria provided, single submitter	clinical testing	Variant summary: DAG1 c.2326C>T (p.Arg776Cys) results in a non-conservative amino acid change located in the dystroglycan, C-terminal domain (IPR008465) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250800 control chromosomes (gnomAD). c.2326C>T has been reported in the literature in the homozygous state in two siblings from a consanguineous family, both affected with muscular dystrophy-dystroglycanopathy (Dai_2019). The variant segregated with the disease phenotype within this family, however both affected individuals exhibited a very mild and very slowly progressing phenotype with a late age of onset, in contrast to previous clinical reports of individuals affected with muscular dystrophydystroglycanopathy (limbgirdle), type C, 9 (MDDGC9). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30450679, 33200426). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.