Submissions for variant NM_001101426.4(CRPPA):c.532G>A (p.Gly178Arg)

gnomAD frequency: 0.00011  dbSNP: rs202108204

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725038	SCV000333431	uncertain significance	not provided	2016-09-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000725038	SCV000536514	uncertain significance	not provided	2021-05-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30564623)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694888	SCV000823354	uncertain significance	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7; Autosomal recessive limb-girdle muscular dystrophy type 2U	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 178 of the ISPD protein (p.Gly178Arg). This variant is present in population databases (rs202108204, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with ISPD-related conditions. ClinVar contains an entry for this variant (Variation ID: 282161). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
Illumina Laboratory Services, Illumina	RCV001159796	SCV001321530	uncertain significance	Congenital Muscular Dystrophy, alpha-dystroglycan related	2018-01-13	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.
Revvity Omics, Revvity	RCV000725038	SCV003828631	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000725038	SCV004228197	uncertain significance	not provided	2018-12-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004021098	SCV004850374	uncertain significance	not specified	2022-02-10	criteria provided, single submitter	clinical testing	The c.532G>A (p.G178R) alteration is located in exon 2 (coding exon 2) of the ISPD gene. This alteration results from a G to A substitution at nucleotide position 532, causing the glycine (G) at amino acid position 178 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796148	SCV005417381	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2U		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3+PP4
PreventionGenetics, part of Exact Sciences	RCV004739653	SCV005361951	uncertain significance	CRPPA-related disorder	2024-03-22	no assertion criteria provided	clinical testing	The CRPPA c.532G>A variant is predicted to result in the amino acid substitution p.Gly178Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.087% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.