Submissions for variant NM_004415.4(DSP):c.7097G>A (p.Arg2366His)

dbSNP: rs387906618

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851996	SCV002240186	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2366 of the DSP protein (p.Arg2366His). This variant is present in population databases (rs387906618, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive skin fragility–woolly hair syndrome (PMID: 20738328). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 29672). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg2366 amino acid residue in DSP. Other variant(s) that disrupt this residue have been observed in individuals with DSP-related conditions (PMID: 11841538), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV003233075	SCV004242418	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-01-15	criteria provided, single submitter	clinical testing	Criteria applied: PP1_STR,PM3,PM5,PM2_SUP,PP3,PP4
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003233075	SCV004804802	likely pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-03-17	criteria provided, single submitter	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV003233075	SCV005045715	likely pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2023-10-04	criteria provided, single submitter	clinical testing
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV003233075	SCV005380261	likely pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma		criteria provided, single submitter	not provided
3billion	RCV003233075	SCV005906281	likely pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2023-06-30	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.20). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with DSP related disorder (ClinVar ID: VCV000029672 /PMID: 20738328). 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: 20738328). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 20738328). A different missense change at the same codon (p.Arg2366Cys) has been reported to be associated with DSP related disorder (ClinVar ID: VCV000016841 /PMID: 11841538). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM	RCV003233075	SCV000043812	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2011-07-01	no assertion criteria provided	literature only