Submissions for variant NM_170784.3(MKKS):c.1307A>G (p.Asp436Gly)

dbSNP: rs746696111

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001140679	SCV001300960	uncertain significance	McKusick-Kaufman syndrome	2018-03-02	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	RCV001140680	SCV001300961	uncertain significance	Bardet-Biedl syndrome 6	2018-03-02	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	RCV001348766	SCV001543081	uncertain significance	Bardet-Biedl syndrome; McKusick-Kaufman syndrome	2022-06-18	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 436 of the MKKS protein (p.Asp436Gly). This variant is present in population databases (rs746696111, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with MKKS-related conditions. ClinVar contains an entry for this variant (Variation ID: 897429). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Fulgent Genetics, Fulgent Genetics	RCV002491422	SCV002792954	uncertain significance	McKusick-Kaufman syndrome; Bardet-Biedl syndrome 6	2021-08-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002556997	SCV003683620	uncertain significance	Inborn genetic diseases	2021-09-27	criteria provided, single submitter	clinical testing	The c.1307A>G (p.D436G) alteration is located in exon 6 (coding exon 4) of the MKKS gene. This alteration results from a A to G substitution at nucleotide position 1307, causing the aspartic acid (D) at amino acid position 436 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV004590105	SCV005078850	uncertain significance	not provided	2023-06-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences	RCV004538360	SCV004116482	uncertain significance	MKKS-related disorder	2024-09-16	no assertion criteria provided	clinical testing	The MKKS c.1307A>G variant is predicted to result in the amino acid substitution p.Asp436Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0070% 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.