Submissions for variant NM_017777.4(MKS1):c.1640C>T (p.Pro547Leu)

gnomAD frequency: 0.00009  dbSNP: rs771585740

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000175339	SCV000226810	uncertain significance	not provided	2017-07-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001125295	SCV001284343	uncertain significance	Meckel syndrome, type 1	2018-01-12	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	RCV001125296	SCV001284344	uncertain significance	Bardet-Biedl syndrome 13	2018-01-12	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	RCV001242967	SCV001416093	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 547 of the MKS1 protein (p.Pro547Leu). This variant is present in population databases (rs771585740, gnomAD 0.01%). 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: 194871). 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 MKS1 protein function. 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.
Genetic Services Laboratory, University of Chicago	RCV001818419	SCV002065603	uncertain significance	not specified	2017-12-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000175339	SCV002513181	uncertain significance	not provided	2023-03-29	criteria provided, single submitter	clinical testing	Observed in homozygous state in a patient with severe neurodevelopmental delays and microcephaly, however this patient also harbored a homozygous variant in the AMPD2 gene (Mitani et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34582790)
Ambry Genetics	RCV002517683	SCV003758222	uncertain significance	Inborn genetic diseases	2022-11-15	criteria provided, single submitter	clinical testing	The c.1640C>T (p.P547L) alteration is located in exon 18 (coding exon 18) of the MKS1 gene. This alteration results from a C to T substitution at nucleotide position 1640, causing the proline (P) at amino acid position 547 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV005016517	SCV005649593	uncertain significance	Bardet-Biedl syndrome 13; Meckel syndrome, type 1; Joubert syndrome 28	2024-06-24	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001125295	SCV002087600	uncertain significance	Meckel syndrome, type 1	2019-10-28	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537381	SCV004756469	uncertain significance	MKS1-related disorder	2024-06-20	no assertion criteria provided	clinical testing	The MKS1 c.1640C>T variant is predicted to result in the amino acid substitution p.Pro547Leu. This variant was reported in the homozygous state in an individual with a neurodevelopmental disorder (Supplementary Table 3, Mitani et al. 2021. PubMed ID: 34582790). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.