Submissions for variant NM_030578.4(B9D2):c.484G>T (p.Gly162Cys)

gnomAD frequency: 0.00002  dbSNP: rs760322583

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
New York Genome Center	RCV001837190	SCV002097671	uncertain significance	Meckel syndrome, type 10	2020-06-26	criteria provided, single submitter	clinical testing	The homozygous c.484G>T (p.Gly162Cys) variant identified in the B9D2 gene substitutes a moderately conserved Glycine for Cystine at amino acid 162/176 (exon 4/4). This variant is found with low frequency in gnomAD(v3.0) (3 heterozygotes, 0 homozygotes; allele frequency:2.09e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms do not agree on the effect of this variant, as it is predicted both Deleterious (Provean; score:-3.31) and Tolerated (SIFT; score:0.124) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:329340) and to our current knowledge has not been reported in affected individuals in the literature. Given the lack of compelling evidence for its pathogenicity, the homozygous c.484G>T (p.Gly162Cys) variant identified in the B9D2 gene is reported here as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002266035	SCV002547600	uncertain significance	not specified	2022-05-11	criteria provided, single submitter	clinical testing	Variant summary: B9D2 c.484G>T (p.Gly162Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 250866 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in B9D2 causing Joubert Syndrome And Related Disorders (6.4e-05 vs 0.0004), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.484G>T in individuals affected with Joubert Syndrome And Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV002275251	SCV002562293	uncertain significance	not provided	2022-02-15	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
Invitae	RCV002545208	SCV003293900	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome	2022-06-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 162 of the B9D2 protein (p.Gly162Cys). This variant is present in population databases (rs760322583, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with B9D2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1341710). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Ambry Genetics	RCV002542795	SCV003734384	uncertain significance	Inborn genetic diseases	2022-08-02	criteria provided, single submitter	clinical testing	The c.484G>T (p.G162C) alteration is located in exon 4 (coding exon 3) of the B9D2 gene. This alteration results from a G to T substitution at nucleotide position 484, causing the glycine (G) at amino acid position 162 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.