Submissions for variant NM_017777.4(MKS1):c.813C>A (p.His271Gln)

dbSNP: rs201961765

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000734184	SCV000862308	uncertain significance	not provided	2018-07-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001126362	SCV001285544	uncertain significance	Meckel syndrome, type 1	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.
Illumina Laboratory Services, Illumina	RCV001126363	SCV001285545	uncertain significance	Bardet-Biedl syndrome 13	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002535372	SCV003486003	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome	2022-06-13	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 271 of the MKS1 protein (p.His271Gln). This variant is present in population databases (rs201961765, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with MKS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 597924). 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 not expected to disrupt MKS1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	RCV003258955	SCV003948794	uncertain significance	Inborn genetic diseases	2023-03-24	criteria provided, single submitter	clinical testing	The c.813C>A (p.H271Q) alteration is located in exon 8 (coding exon 8) of the MKS1 gene. This alteration results from a C to A substitution at nucleotide position 813, causing the histidine (H) at amino acid position 271 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV005021141	SCV005647359	uncertain significance	Bardet-Biedl syndrome 13; Meckel syndrome, type 1; Joubert syndrome 28	2024-03-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535875	SCV004742369	uncertain significance	MKS1-related disorder	2024-01-16	no assertion criteria provided	clinical testing	The MKS1 c.813C>A variant is predicted to result in the amino acid substitution p.His271Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.